Pyrimidine derivatives and methods of making and using these...

Details Pyrimidine derivatives and methods of making and using these... Pyrimidine derivatives and methods of making and using these...

2000-05-04

2001-04-24

Shah, Mukund J. (Department: 1624)

Drug, bio-affecting and body treating compositions

Designated organic active ingredient containing

Having -c-, wherein x is chalcogen, bonded directly to...

C514S183000, C544S280000

Reexamination Certificate

active

06221872

ABSTRACT:

BACKGROUND OF THE INVENTION
1. Field of the Invention
This invention relates to pyrimidine derivative compounds and pharmaceutically acceptable salts thereof. More specifically, this invention relates to furo[2,3-d]pyrimidines, pyrrolo[2,3-d]pyrimidines, pyrrolo[3,2-d]pyrimidines, pyrrolo[3,4-d]pyrimidines, thieno[2,3-d]pyrimidines, cyclopentapyrimidines and cyclopenta[d]pyrimidines. These compounds have been found useful in resisting and treating Pneumocystis carinii and Toxoplasmosis gondii infections in immunocompromised patients, such as, for example, patients with autoimmune deficiency syndrome (AIDS). These compounds are also useful as potential antitumor, antibiotic, antimalarial, antifungal or antiprotozoal agents, or as synergistic agents when used with sulfonamides may require the use of leucovorin rescue. These compounds are also useful as antitumor agents in cancer patients. Methods of preparing and using these compounds are also provided.
2. Description of the Background Art
Various pyrimidine systems, such as the pyrido[2,3-d]pyrimidine ring system, have been studied due to their involvement in the inhibition of dihydrofolate reductase (DHFR) enzymes activity. The pyrimidine derivatives disclosed herein function as DHFR inhibitors. Because DHFR reduces dihydrofolate to tetrahydrofolate, inhibition of DHFR deprives the cell of tetrahydrofolate, without which the cell cannot produce 5,10-Methylenetetrahydrofolate. 5,10-Methylene-tetrahydrofolate is essential for cell growth. The inhibition of DHFR by the compounds, and pharmaceutically acceptable salts thereof, of this invention results in the inhibition of DNA synthesis and leads to cell death. Methotrexate (MTX), trimetrexate (TMQ), piritrexim (PTX) and other folic acid analogues function as inhibitors of cell growth by similar mechanisms involving the inhibition of dihydrofolate reductase.
The pyrimidine derivatives disclosed herein further function as thymidylate synthase (TS) inhibitors. TS, along with DHFR, forms part of the systems responsible for the synthesis of deoxythymidylate (dTMP) from deoxyuridylate (dUMP). TS catalyzes the sole de novo synthesis of dTMP from dUMP. Inhibition of TS, therefore, deprives the cell of thymidine, which is an essential constituent of DNA. Typically, the compounds as described herein where X and Y are both NH
2
will function as DHFR inhibitors, and compounds where X is OH and Y is NH
2
will function as TS inhibitors.
Drugs useful for the reduction of cancerous cells are also known.
Elslager, Edward F., et al., “Folate Antagonists. 20. Synthesis and Antitumor and Antimalarial Properties of Trimetrexate and Related 6-[(Phenylamino) methyl]-2,4-quinazolinediamines”
J. Med. Chem
., Vol. 26 pp. 1753-1760 (1983)), discloses the preparation of quinazolinediamines. This article states that the quinazolinediamines exhibit potent antimalarial, antibacterial and antitumor activity.
Methods of synthesizing diaminopyrido[2,3-d]pyrimidines having various substituents are known. See Hurlbert, B. S., et al., “Studies on Condensed Pyrimidine Systems. XXIII. Synthesis of 2,4-Diaminopyrido[2,3-d]pyrimidines from 6-Keto Esters”,
J. Med. Chem
., Vol. 11, pp. 703-707
9
1968), and Hurlbert, B. S., and Valenti, B. F., “Studies on Condensed Pyrimidine Systems. XXIV. The Condensation of 2,4,6-Triaminopyridimine with Malondialdehyde Derivatives”,
J. Med. Chem
., Vol. 11, pp. 708-710 (1968).
Hurlbert, B. S., et al., “Studies on Condensed Pyrimidine Systems. XXV. 2,4-Diaminopyrido[2,3-d]pyrimidines. Biological Data”,
J. Med. Chem
., Vol. 11, pp. 711-717 (1968), discloses the antimicrobial activities of several subgroups of pyridopyrimidines. This article states that 2,4-diaminopyrido[2,3-d]pyrimidines bearing alkyl and aralkyl substitutes in the pyrimidine moiety are inhibitors of dihydrofolate reductase having antibacterial and antiprotozoal activity and that these compounds potentiate sulfonamides.
Grivsky, E. M., et al., “Synthesis and Antitumor Activity of 2,4-Diamino-6-(2,5-dimethoxybenzyl)-5-methylpyrido[2,3-d]pyridimine”,
J. Med. Chem
., Vol. 23, pp. 327-329 (1980), discloses the synthesis of 2,4-diamino-6-(2,5-dimethoxybenzyl)-5-methylpyrido[2,3-d]pyridimine(BW301U,7). This article states that BW301U,7 is as effective as methotrexate as an inhibitor of dihydrofolate reductase purified from human luekemic cells and, in contrast to metoprine, has minimal activity as an inhibitor of histamine metabolism.
Werbel, Leslie, M., et al., “synthesis and Antimalarial Activity of a Series of 2,4-Diamino-6-[(N-alkylanilino)methyl]quinazolines [1,2]”,
J. Heterocyclic Chem
., Vol. 24, pp. 345-349 (1987), discloses the synthesis of N6 substituted quinazoline dihydrofolate reductase inhibitors. This article states that these analogs demonstrate substantial activity against Plasmodium berghei infections in mice.
Piper, J. R., et al., “syntheses and Antifolate Activity of 5-Methyl-5-deaza Analogues of Aminopterin, Methotrexate, Folic Acid, and N
10
-Methylfolic Acid”,
J. Med. Chem
., Vol. 29, pp. 1080-1087 (1986), discloses that 5-methyl-5-deaza analogues of aminopterin and methotrexate are much more growth inhibitory than methotrexate.
Pyrido [2,3-d] and [3,2-d] pyrimidines are also disclosed in U.S. Pat. Nos. 5,346,900 and 5,508,281, and co-pending application Ser. No. 08/515,491, all of which are hereby expressly incorporated by reference.
Pyrrolo[2,3-d]pyrimidines are disclosed by Gangjee et al. in “Novel 2,4-diamino-5-substituted-pyrrolo[2,3-d]pyrimidines As Classical and Non-Classical Antifolate Inhibitors of Dihydrofolate Reductases”,
J. Med. Chem
., Vol. 38, pp. 2158-2165 (Jun. 6, 1995).
Gangjee, A., et al., “Classical and Non-Classical Furo[2,3-d]-Pyrimidines As Novel Antifolates: Synthesis and Biological Activities”,
J. Med. Chem
., Vol. 37, pp. 1169-1176 (1994), discloses the furo[2,3-d]pyrimmidines.
In spite of the art discussed above, there remains a very real and substantial need for compounds that are more active and more selective than known compounds at resisting and treating infections caused by Pneumocystis carinii and Toxoplasmosis gondii in immunocompromised patients, reducing the tumor size and/or the number of cancerous cells in cancer patients, and for methods of preparing and using such compounds.
SUMMARY OF THE INVENTION
The present invention has met the above described need. The present invention provides pyrrolo[2,3-d]pyrimidine compounds, and pharmaceutically acceptable salts thereof, having the formula (1):
wherein X and Y are the same or different and are selected from the group consisting of OH and NH
2
;
wherein L and M are selected from the group consisting of carbon and CH, the chemical bond between L and M is selected from the group consisting of a single bond and a double bond, L and M are carbon when the bond is a double bond, and L and M are CH when the bond is a single bond;
wherein Z
2
and Z
3
are different and are selected from the group consisting of R
4
and
where Z
2
is R
4
when Z
3
is
and Z
2
is
when Z
3
is R
4
;
wherein A is selected from the group consisting of CH and zero;
wherein B is selected from the group consisting of CH, nitrogen, N—CH
2
, CH
2
—N, CH
2
—CH
2
, oxygen and sulfur;
wherein R
1
is selected from the group consisting of hydrogen, a lower alkyl group, a nitroso group, a formyl group and zero and R
1
is zero when B is oxygen or sulfur;
wherein R
3
is selected from the group consisting of hydrogen, a lower alkyl group and zero, and R
3
is zero when A is zero;
wherein R
4
is selected from the group consisting of hydrogen and a lower alkyl group;
wherein R
5
is selected from the group consisting of hydrogen and a lower alkyl group;
wherein R
8
is selected from the group consisting of naphthyl, mono-, di- and tri-substituted naphthyl, thionaphthyl, thiophenyl and hydroxyphenyl when R
1
is hydroge

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